Shares of TG Therapeutics Inc. plunged 44.3 percent to $5.15 on Tuesday as uncertainty over timing of a key interim readout for its two-drug chronic lymphocytic leukemia (CLL) treatment led it to scrub plans to seek accelerated approval for the combo.
The phase III trial, UNITY-CLL, is testing an anti-CD20 monoclonal antibody, ublituximab, in combination with a PI3K-delta inhibitor, umbralisib, vs. an active control arm of Gazyva (obinutuzumab, Roche Holding AG) plus chlorambucil. New York-based TG said its team will now focus on seeking a full approval, based on progression-free survival data, which are expected to arrive next year.
At the heart of the change was news from an independent data safety monitoring board (DSMB). It told the company that a planned interim analysis of overall response couldn't be conducted because the board felt the data weren't sufficiently mature, company Chairman, CEO and President Michael Weiss said. Neither further guidance nor color on the choice were conveyed, according to the company.
With TG's executives still blinded to efficacy data, they were left to think "hard and realistically" about the potential for an accelerated approval filing, Weiss said, during a Tuesday conference call. "We just felt that whether overall response is openly positive or not, the delays in getting to mature enough overall response data continue to narrow the gap between potential overall response filing and a PFS filing and, thus again, continued reliance on that endpoint for a rapid path to approval seem misguided," he said.
Focusing on PFS, an event-driven readout that could support a BLA filing as early as the middle of next year, is an important step in "getting everyone aligned with the trial endpoint that matters most to the company and provides the most value to its long-term shareholders," Weiss said.
Meanwhile, the DSMB plans to meet quarterly over the next year to continue to monitor the ongoing progress of the trial, reaching out as needed as it continues to monitor the ongoing progress of the trial.
UNITY-CLL is a randomized controlled trial comparing the combination of ublituximab plus umbralisib, or U2, to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment-naive and relapsed or refractory CLL. It's being conducted under a special protocol assessment (SPA) with the FDA.
The trial randomized patients into four treatment arms: ublituximab single agent, umbralisib single agent, ublituximab plus umbralisib and an active control arm of Gazyva plus chlorambucil. A prespecified analysis was conducted to assess the contribution of ublituximab and umbralisib in the combination regimen of ublituximab plus umbralisib and allowed for the termination of the single-agent arms.
Once that analysis was complete, the trial continued enrollment in a 1-to-1 ratio into the two combination arms: the investigational arm of U2 and the control arm of Gazyva plus chlorambucil.
Full enrollment into the trial was completed in October 2017 with treatment-naive CLL patients comprising about 60 percent of the study group and relapsed refractory CLL patients accounting for the other 40 percent. The primary endpoint for the study is to demonstrate superiority in PFS for the U2 combination over the control arm to support the submission for full approval.
On the subject of safety, a topic the DSMB didn't opine on in its communication with TG, Weiss seemed to suggest that sometimes no news is good news. "We can only speculate that they didn't see anything in the safety database and the PFS profile that gave them pause that this study should be stopped for any benefit-risk issue," he said.
At June 30, the time of its last quarterly report, TG had cash and equivalents of $126.3 million. Burn at the company will be largely unaffected, Weiss said. Though some expenses could "smooth out," he allowed, no savings or cost increases were expected.
Including the UNITY-CLL trial, TG now has five fully enrolled registration-directed programs. Its multifaceted UNITY-NHL is evaluating single-agent umbralisib and building toward evaluating double and potentially triple combinations using U2 as the backbone across a variety of subtypes of non-Hodgkin's lymphoma. Meanwhile, its ULTIMATE MS program is running two identical phase III trials under an SPA with the FDA, evaluating ublituximab in relapsing forms of multiple sclerosis.
TG also recently entered an exclusive global license agreement with Geneva-based Novimmune SA to collaborate on the development and commercialization of Novimmune's anti-CD47/anti-CD19 bispecific antibody, TG-1801 (previously NI-1701). (See BioWorld, June 21, 2018.)